Aileen Caceres, MD: Thank you very much that was a great keynote. I wanted to start my discussion with an anecdote of why, now that I have a couple of minutes to spare, why I was aspired to actually proceed with considering the visual diagnosis of endometriosis with Firefly. That really came from patients that were referred to our practice who had had multiple laparoscopies and never really had a diagnosis. Here I was struggling with these patients and trying to help them understand their chronic pelvic pain without truly having had a diagnosis of endometriosis. This is how things got started on this.

With no further ado; no disclosures for myself.

As we know, endometriosis is a common condition that affects most reproductive age women and we know that it affects approximately one in 20. We see this in the center, especially where we have a large referral basis, especially from our reproductive endocrinologists and also from our primary care physicians who are quite savvy in terms of trying to pick up these conditions. We also know that endometriosis at the time of laparoscopy can and cannot be diagnosed. It ranges, from five percent to 24 percent. And the studies are everywhere in terms of that detection rate.

Surgical advances have helped us to help identify endometriosis but again that can vary and as noted by our pathologist when we have ablation techniques sometimes we may not be able to give the diagnosis of endometriosis but visually we should be able to detect these lesions. With excisional surgery we have the ability as noted, especially with endometriomas to resect these and grab that opportunity as early as we can to proceed forward helping women with those chronic pelvic pain syndromes. Visual diagnosis varies in its accuracy. We have many different ways that we can tell endometriosis from the naked eye utilizing white light laparoscopy to utilizing the robot and the white light. Also, visualizing without any additional aids, but this can be quite challenging and it can vary from each of the modalities.

With that, indocyanine green has actually been used over the last 20 years and it has actually been used with cardiac and cardiovascular conditions. It notes cardiac output, heart failure. It has also been utilized in knowing the integrity of graphs so we know the vascular and we know the angiogenic basis of it.

To some basics, its peak spectral flow is noted at 800 nanometers and it occurs when we note at the deeper layers the penetration of the wave lengths. It binds tightly to plasma proteins and it becomes confined to the vascular system. So we are thinking about the vascular or the angiogenic process and it is involved when we are thinking about endometriotic lesions and that is why I want you guys to focus. The half-life is 150 to 180 seconds and it is removed exclusively by the liver. It has safely been used over the last 20 years.

The role of endometriosis and ICG dye is really based on the angiogenic properties or the angiogenic basis of the differential or the diagnosis of endometriosis. If we can have an impact or visualization of endometriosis early enough when it occurs at this angiogenic level perhaps we can see lesions that are greater and that are more expansive and this is really where this study has taken us.

The purpose of this study is to take a look at three comparative methods and the three comparative methods utilized were white light laparoscopically switched over to robotic white light 3D visualization. Then we inject the ICG dye and we give it as a bonus injection and then we visualize the lesions in a map related way utilizing robotic Firefly ICG dye influence. So there are three modalities of visualization.

We are conducting a comparative prospective, single-center, ongoing observational study. And I said the primary objective is to compare if there is any difference in visualizing these lesions with the three modalities that I just explained. The secondary objective is to identify of course quality of life and levels of pain for patients having endometriosis and providing that six month to a year follow up. We use pre-menopausal women 18 to 55 with symptoms of endometriosis including dysmenorrhea, dyspareunia, chronic pelvic pain of greater than six months duration, pressure on the bladder or the rectum causing painful bowel movements and infertility.

We excluded patients who had an allergy to the dye or to shellfish, presence of medical conditions contraindicating general anesthesia or robotic surgery which involves deep trendelenburg position, any active pelvic infections obviously, radiation therapy or anybody who you have a concern for a malignancy. Measurements pre-operatively, informed consent, demographics, medical history, pain scale and quality of life – we used the RAND SF-36. And intra-operatively we developed a map where we sequentially analyzed every section of the pelvic region starting in the central bladder region and all the way to the posterior cul-de-sac underneath the ovarian foci including the appendix, following that to the left uterosacral ligament, the left pelvic sidewall and then following that up all the way to the bladder again.

We quantify and we anatomically locate where the lesions are and we have maps for doing that. We estimate the width of the lesion and that of course has only been done by me as the only surgeon that has been doing these procedures at my hospital. Then we start, as I said previously, we start with the visualization that is done laparoscopically in a sequential, clockwise manner throughout the pelvis. We switch over to 3D robotic white light. So I am comparing white light laparoscopic 2D to white light robotic 3D and then we inject the dye and we compare that to the prior two and now it is with the Firefly dye. Then the Da Vinci is utilized to then excise any lesions that are noted.

Post-operative assessment – immediate post-op histopathology, so every specimen gets labeled in terms of the location because we want to map whether there has been a concurrency in terms of location. All of that gets sent sequentially to pathology and then a quality of life scale and pain scale that the patients are followed with.

Just to give you visualization. I do not know if many of you guys do Firefly but on the SI the pictures do not project very well, they are very dark. This is actually from the XI and I am afraid these are not projecting well either. But if you noticed in this pelvis we started off with the white light, the white light, doing a survey. This is after injecting the dye. We used one to two milligrams and it is injected as an IV bolus. We work very closely with our anesthesiologist and you start seeing a conglomeration of green all throughout the pelvis. What this denotes is the right uterosacral ligament with a lesion that in this patient was identified to be about half a millimeter larger with the Firefly. Again, I apologize these do not project very well. But the whole concept involves that we see the angiogenic effect of the dye as it binds to the plasma proteins. In some of the patients that we have done this in we actually see an extension of that halo effect from the ICG dye. Pathology reports have matched that to a mesothelial reaction and early presence of endometriosis.

Yes sir. (Audience question). I am sorry, this would have been the normal shot in the white light you mean? (Audience response: too far away…) I know. I do not have very good pictures for comparison. That is a great point.

This kind of gives us patient characteristics. Most of our patients are in the mid-30s with a BMI of 28, an ASA of 1.9. Patients with previous endometriosis 43 percent that have been treated but not surgically confirmed endometriosis, and percent of adhesions about 86 percent of our patients. Mind you this is an n of seven so our trial is very small, we are currently recruiting so it is only seven patients. A pain scale of 5.3 is to be expected for patients in this category. Quality of life measures: definitely ranging physical functioning limitations, fatigue, social functioning affected. The quantity of lesions and the comparison between the 2D white light versus 3D white light versus Firefly. We see that statistically significant difference in the amount and the size of lesions that we are noting.

The preliminary data, and again this is preliminary data, patients with endometriosis prior to resection have a relatively high level of pain. Overall quality of life is low, particularly in regard to physical quality of life. In terms of endometriosis and Firefly utilization total number of visualized lesions with Firefly imaging is 3.6 times greater than D1 or a 2D white light imaging and two times higher than a 3D white light imaging. This preliminary data suggests that there may be a role for utilizing ICG dye in terms of angiogenic effect on endometriosis visualization and perhaps give us a key to the early diagnosis and now perhaps identification.

We are currently on ClinicalTrials.gov recruiting patients and again we have seven patients that are part of this trial so far. Any questions?

Harry Reich, MD: We saw the 1Ks and we like to spend lots of money in our country on our diagnosis and our techniques sometimes. My question is, on exam, it looked like it could really be able to feel that uterosacral ligament quite well with a rectovaginal exam, elevating the cervix and feeling there. Was that the area of pain pre-operatively?

Aileen Caceres, MD: Actually this patient had pain on the left hand side and that lesion was on the right. She did not have any nodularities so I was quite surprised quite honestly when I found this lesion on the right instead of the left. I had some suspicion because this patient has been living with chronic pelvic pain for over ten years, and infertility. I finally said to her in terms of the delay of diagnosis that we have all heard about we perhaps need to take a look, you may be a candidate for our Firefly study. So, yes, it was on the left for her.

Harry Reich, MD: Did she get better?

Aileen Caceres, MD: You know what, she was actually two weeks ago – we have not reached out to her yet, but I will tell you from the earlier cases that I did not present and I wish I could have delineated every case, I just did not have enough time for that, but the first patient has been out almost a year and has been doing fantastic with this. The first patient was a patient who had undergone three laparoscopies in the past, no endometriosis was noted at that time, and presented with rectal bleeding, had a colonoscopy. But she is doing much better now.

Harry Reich, MD: I ask the question because I think it is important to give a little clinical and now with the medical records being so computerized it is good to at least feel the patient. Thank you very much.

Robert Taylor, MD: Very nice presentation. This is Rob Taylor here. I congratulate you on the study. A couple of comments; one actually has to do with this – so we heard actually on all three of the lectures this morning we heard a lot about angiogenesis. One of the interesting things about angiogenesis around these lesions is that the blood vessels are actually quite leaky in the region of the lesion, much more so the normal blood vessels. So actually having a dye that binds tightly to plasma proteins might be a disadvantage in this type of an approach and I would suggest that if there was a dye that was not so tightly bound they could actually diffuse out through the fenestrations that are going to be around these lesions. What you might predict is that there would be kind of a halo effect around and it might allow you to actually see lesions that you do not visualize. So, at least kind of technologically you might think a little bit more about this.

The other comment is the study design is sort of biased to see a preference for your dye study because you are doing this progressive thing with the mapping of the lesions. If you did not see them the first time you might see them with the robotic 3D so you are going to have a little bit of an analytical, sort of challenges with that. I do not think you can do them in random order but that would be the other way to get around it.

Aileen Caceres, MD: Exactly, exactly, or have other surgeons as well join us in the study so we have a varying pool, absolutely.

Tamer Seckin, MD: Thank you very much. It is interesting but there is some as is pointed out, I feel bias here. Not only the dye, those are assistant robots. I do not see any place of robots with this particular technology. I think they are separate issues. A robot does not shake, a robot – there is a…there. And the only thing I dislike of what is being proposed is selling an item about robot is it is 3D and it is better visualization. I use both, that is totally nonsense. I can see as well, as well as good and even better because I can bring my camera and kiss the tissue. You guys cannot get near to the tissue. I will conclude there.

Aileen Caceres, MD: What do you mean, robotically?

Tamer Seckin, MD: You can come very close to the tissue and magnify tremendously. With a robot you cannot. It is hot, the tip, can you touch the tissues?

Aileen Caceres, MD: You can get pretty close to the tissue.

(Cross talk - illegible)

Tamer Seckin. MD: Well, if you bring closer you can get 30 times, 40 times magnification with regular laparoscopy.

(Cross talk - illegible)

Aileen Caceres, MD: Very close. Right on top. On the tissue, right up against.

Moderator: We have time for one more question.

Andrew Cook, MD: I will try to be brief. This is a follow up of Dr. Seckin in his presentation this morning. I think that we are talking about diagnosis and I think it cannot be over emphasized the systematic technique in the near contact and whether retroperitoneal dissection and really getting the light reflections right. So just to be so meticulous in evaluation of the peritoneum as I do believe that this “minimal” endometriosis can have huge amount of pain and you have to diagnose it. If you miss it, and it is easy to miss, take that time and look by whatever technique people end up using.

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